Anthranilic acid amides and derivatives thereof as cosmetic and pharmaceutical agents

ABSTRACT

The use of specific compounds of the Formula 1 (and also corresponding mixtures)  
                 
in particular as cosmetic agents for the inhibition of the substance P-induced release of histamine from mast cells is described.

The present invention relates to specific uses of compounds of theFormula 1 or of mixtures of two or more different compounds of theFormula 1.

The invention also relates to selected compounds of the Formula 1 thatwere not known hitherto.

A first aspect of the present invention relates to a use of a compoundof the Formula 1 or of a mixture of two or more different compounds ofthe Formula 1 as a cosmetic agent for inhibiting the release ofhistamine from mast cells that is induced by the substance P or for thepreparation of a medicament for the inhibition of the release ofhistamine from mast cells that is induced by the substance P.

In this context the following applies for the compound of the Formula 1and for each compound of the Formula 1 in the mixture:

m=0, 1, 2 or 3,

p=0, 1 or 2,

n=0, 1 or 2,

with the proviso that, when n=1 or 2, the sum of p+m >0,

where, when n=1 or 2, R¹ and R², in each case in pairs, in each casedenote H or together denote a further chemical bond (such as, forexample, in cinnamic acid derivatives);

where, when m=1, 2 or 3, each X, independently of the others, denotesOH, Oalkyl or Oacyl,

where, when p=1 or 2, each Y, independently of the others, denotes OH,Oalkyl or Oacyl,

with the proviso that, when p+m >0, X or Y has been selected at leastonce from the group that consists of OH and Oacyl;

R³═H or alkyl (in particular —CH₃, as well as straight-chain or branchedalkyl chains with 2 to 30 C atoms)

In this context R³═H for the corresponding pharmaceutically acceptablesets (sic) as well.

In this context, a compound of the Formula 1 can be in the form of anarbitrary isomer or mixture of isomers, thus for example, for n=1 andR¹, R²=further chemical bond, in the form of the cis or trans-isomer.

For X or Y=Oacyl, preferably: acyl=CO—R where R=—CH₃, or astraight-chain or branched alkyl radical with 2-30 C atoms.

Mast cells play an essential role in allergic and inflammatory processessince, after corresponding stimulation, they release mediators such ashistamine that to a large extent are responsible for symptoms such asitching (pruritus), pain or reddening reactions. Numerous studies havebeen able to show that the neuropeptide substance P, which is releasedby nerve ends in the skin, gives rise to a degranulation of mast cells.Thus, substance P can be regarded as one of the most importantconnecting links between the peripheral nerve system and symptoms suchas inflammatory processes, itching and pain.

In the pharmaceutical and cosmetics industry there is an ongoing needfor histamine release inhibitors. The uncontrolled release of highhistamine concentrations is accompanied by symptoms such as itching,pain or reddening reactions. A clear correlation between histaminerelease and severe itching has been established in particular in thecase of urticaria (nettle rash). The name urticaria is historicallyderived from the symptoms, which can be observed after contact of theskin with stinging nettles (latin name: Urtica dioica L.) (itching,burning and the development of weals). In this particular case, interalia, histamine already contained in the stinging nettle, which isstored in special secretion organs and after contact with the skin isinjected into the skin via the so-called stinging hairs, which are inthe form of an injection needle, has an effect. The result is reddening,itching and the development of weals.

One feature is common to the various forms of urticaria, i.e. theactivation of a special type of cell, the so-called mast cells. Mastcells can also be said to be the “fire brigade” or “border police” ofthe human body. They are to be found particularly frequently inlocations where we come into direct contact with our environment, thatis to say, as well as in the skin, also in the mucus membranes of thegastrointestinal tract and the respiratory tract. Activation of the mastcells by various mediators (immunoglobulins such as IgE or neuropeptidessuch as substance P) can be accompanied by severe inflammatoryreactions, itching and severely allergic reactions extending toanaphylactic shock. For this purpose the mast cells produce a widevariety of products, including histamine. These products are stored bythe cells in storage vessels, the so-called granula, and on activationare released in a large quantity into the skin. This, in turn,—andhistamine has a particularly important role here—leads to the bloodvessels becoming “leaky” at the point in the skin concerned and bloodconstituents (mainly fluid) penetrating into the tissue. A weal isproduced as a result. In addition, widening of the blood vessels(vasodilation) takes place. Consequently, there is greater perfusion ofblood through the skin regions concerned, which leads to reddening. Theproduction of itching is explained as follows: on the one hand, theliberation of histamine from mast cells leads directly to itching. Onthe other hand, histamine and other mast cell products stimulate nervefibres in the skin. This stimulation now has the result that the nervefibres release substances that initiate itching (so-calledneuropeptides). These neuropeptides (for example substance P) are, inturn, good mast cell activators, so that the stimulation of nerves bymast cells results in a stimulation of mast cells by nerves. In the skinand in mucous membranes, mast cells are preferably localised in theimmediate vicinity of vessels and nerves. Thus, it is no surprise thatthe communication between the “neighbours” mast cells, vessel cells andnerve fibres functions extremely well.

Itching, which is partly to be ascribed to the release of highconcentrations of histamine from mast cells, can arise in variousillnesses. These include essentially allergic skin reactions (foodallergies, chemicals), pruritus (nettle rash), contact with plants (forexample stinging nettles), insect bites, psoriasis, infections and minorburns, healing injuries, physical stimuli, such as heat or mechanicalfriction and nickel allergy.

Surprisingly, it has been found in extensive research carried out by theApplicant that the abovementioned compounds of the Formula 1 andmixtures of two or more different compounds of the Formula 1 areoutstandingly suitable for inhibiting the release of histamine from mastcells induced by substance P. Selected research results are summarisedfurther below in the form of examples and tables.

Amongst the compounds of the Formula 1 that can be used according to theinvention, certain sub-groups and individual substances are particularlysuitable for inhibiting the release of histamine from mast cells inducedby the substance P. These preferred sub-groups and individual substancescan be seen from the dependent claims, the examples below and theassociated tables.

According to a second aspect of the present invention, it has beenfound, surprisingly, that certain compounds of the Formula 1 or mixturesof two or more different compounds of the Formula 1 can be used not onlyfor the inhibition of the release of histamine from mast cells inducedby the substance P but also, more generally, for the treatment orprevention of itching (pruritus), skin reddening, development of wealsand/or allergic skin reactions (and also for the preparation ofcorresponding medicaments).

In general it is true that the compounds of the Formula 1 indicatedabove as suitable for inhibition, according to the invention, of therelease of histamine from mast cells induced by the substance P, canalso be used for the more general purpose of the treatment or preventionof itching, skin reddening, development of weals or allergic skinreactions.

However, to this extent as well, certain compounds of the Formula 1 arepreferred, which can be seen from the dependent claims, the examples andthe associated tables.

In this context it is pointed out that itching is not only related tothe mechanisms indicated above, but is also brought into relation withdry skin, senile skin, mechanically or chemically stressed skin or skinstressed by sunlight. Furthermore, psychological factors such as anxietyor stress can cause itching. Soaps, cleaning agents and solvents thatplace a severe stress on the skin can lead to a disturbed hydrolipidfilm and cause itching reactions as a result. Itching can also ariseduring the healing process of injuries or burns (for example aftershaving or after sunburn), so that here as well the application ofcosmetic formulations that prevent or alleviate itching can contributeto preservation of an optimum physiological condition of the skin. Inaddition, there is the broad field of cosmetic products that are used onaging skin. Although the fundamental biochemical processes of itchingand reddening reactions have not been clarified in detail, there arefindings that histamine plays an essential role here as well.

It is therefore easy to comprehend that there is considerable interestin pharmacy and in the cosmetics industry in discovering activecompounds that inhibit the release of histamine from mast cells and/orcan be used for the treatment or prevention of itching, skin reddening,development of weals or allergic skin reactions.

The compounds of the Formula 1 according to the invention or themixtures of two or more different compounds of the Formula 1 can be inthe form of a constituent of a plant extract, which has been subjectedto after-treatment if necessary. In particular, the plant extract, whichhas been subjected to after-treatment if necessary, can be an extractfrom plants from the genus Avena, Dianthus, Silene or Melandrium, inparticular oat extracts or carnation extracts.

If a plant extract is after-treated, this preferably ensures that theproportion of one or more compounds of the Formula 1 relative to theproportion of other extracted components is increased, compared with theextract that has not been after-treated.

Although this is not necessary in all cases, it is nevertheless in somecases advantageous to use an isolated and purified compound of theFormula 1 or an isolated and purified mixture of two or more differentcompounds of the Formula 1 for the said intended uses. The isolation andpurification of compounds of the Formula 1 or corresponding mixturesfrom a plant extract are to be regarded as an after-treatment in whichthe proportion of compounds of the Formula 1 relative to the proportionof other extracted compounds is increased.

Finally, according to a further aspect, the present invention alsorelates to selected compounds of the Formula 1 that can be used for theintended purposes and were not known hitherto. These novel compoundsaccording to the invention can be seen from the appended tables.

With regard to the state of the art, the following is pointed out:

Inter alia, the following therapeutic measures are already known for thealleviation of weakly pronounced itching: medicinal oil baths containingsoya bean oil (Balneum hermal), liquid paraffin (oleatum fat) orγ-linolenic acid (linola fat oil bath), body creams (W/O emulsions inthe form of lotions), such as, for example, Bepanthenol Roche Lotion For Eucerin cum aqua, body oils containing almond or jojoba oil andpreparations containing moisture retention factors, such as, forexample, urea or salicylic acid. In the case of strongly pronouncedexanthemata/weals, steroid-containing external agents are applied, forexample.

Active compounds which have an itch-alleviating activity based on atargeted inhibition of the mediator-induced liberation of histamine frommast cells include, for example, disodium chromogycate, verapamil,ketotifen or tranilast. The substance known under the trade nameTranilast is N-(3,4-dimethoxy-cinnamoyl)anthranilic acid, a naturalanthranilic acid amide occurring in the Chinese medicinal plant Nandinadomestica, which, however, does not fall under Formula 1.

Possibilities for the use of tranilast in the case of allergicreactions, such as bronchial asthma, allergic rhinitis, allergicconjunctivitis, food allergies, urticara or atopic dermatitis arereported in various patents and publications (DE 2402398; EP 0074725;U.S. Pat. No. 4,070,484; H. Shioda et al., Allergy 34, 213-119 (1979);M. Kojima et al., Oyo Yakuri 28(4), 623-628 (1984), Azuma et al., Br. J.Pharmacol. Vol. 58, p. 483-488, (1976); Koda et al., Int. Archs. Allergyappl. Immun. Vol. 77, p. 244-245, (1985); Komatsu et al., Japan J. ofPharmacol. Vol. 46, 43-51,(1988); Hachisuka et al, Arch. Dermatol. Res.Vol. 280, p. 158-162, (1988).

As Komatsu et al report, tranilast inhibits the antigen-(DNP ascaris;monoclonal IgE antibody with 2,4-dinitrophenyl-specificity) inducedrelease of histamine from mast cells in the concentration range of 10⁻³to 10⁻⁵M. It was possible to achieve 50% inhibition of the histaminerelease at a concentration of approximately 10⁻⁴ M. On the other hand,the influence of other anthranilic acid amides on the inhibition of therelease of histamine from mast cells was not described in thepublication.

Hachisuka et al. (Arch. Dermatol. Res. Vol. 280, p. 158-162; 1988)investigated the influence of various active compounds on the inhibitionof the substance P-induced release of histamine from mast cells. Herethe activity of disodium chromogylcate (sic), ketotifen and tranilastwas compared. It was possible to achieve 50% inhibition of the substanceP-induced histamine release only at a relatively high concentration ofapproximately 10⁻³ M. For a molecular weight of tranilast of 327, 10⁻³Mcorresponds to a concentration of 327 μg/ml or 327 ppm. The value forDSCG (disodium cromoglycate), a known antiallergic agent, was in acomparable concentration range (41% inhibition at 10⁻³ M). Otheranthranilic acid amides were not investigated in more detail within theframework of this research work either.

Kojima Masami et al. (Oyo Jakuri, 28(4), p. 623-28; 1984) describe theanti-allergic action of other anthranilic acid amides, such as, forexample, a tranilast demethylated in the 4-position(N-(3-methoxy,(sic)4-hydroxycinnamoyl)anthranilic acid), which, however,is said to have an inhibitory effect only equal to that of tranilast.

In U.S. Pat. No. 4,070,484 it is described that the oral application ofmonosubstituted N-(4-hydroxycinnamoyl)anthranilic acid in a dose of 200mg/kg effects a 36.7% inhibition of antigen-induced destruction of ratmast cells, in contrast with which the corresponding (dimethylated)tranilast (N-(3,4-dimethoxycinnamoyl)anthranilic acid) displays adistinctly higher inhibition rate, i.e. 46.1%, under identical testconditions. Comparative values relating specifically to the inhibitionof the substance P-induced release of histamine from mast cells are notgiven in the document.

Anthranilic acid amides are described as constituents of certain plants,such as, for example, oats (Avena sativa) or carnations (Dianthus sp.).

The avenanthramides of oats are acid amides consisting of unsubstitutedor substituted anthranilic acid partial structures and unsubstituted orsubstituted cinnamic acid partial structures, whilst, on the other hand,the acid amides in carnation species are essentially composed ofanthranilic acid partial structures and benzoic acid partial structures.Plant physiological studies showed that both the so-calledavenanthramides of oats and also the so-called dianthramides incarnations act as phytoalexins and are formed by the plant aftermicrobial infestation as part of a defence mechanism.

The use of oat extracts to alleviate itching has long been known in folkmedicine and is mentioned in the following documents: Hagers Handbuchder Pharmazeutischen Praxis, Vol. 4, published by R. Hänsel, K. Keller,H. Rimpler, G. Schneider, Springer Verlag, Berlin, 1992, p. 437-446; USFederal Register Oct. 3, 1989; 54, 190 proposed rules, pp 40808-40811;Bundesanzeiger No. 193, 15.10.1987). The use of specific yeast extractfractions with an enriched content of anthranilic acid amides toalleviate itching and skin reddening has been described in a more recentpublication (J. Vollhardt et al., Proceedings of the XXIst IFSCCInternational Congress, Berlin, Sep. 11-14, 2000, p. 395; Verlag fürChemische Industrie, H. Ziolkowsky GmbH Augsburg Germany). However, thispublication does not report which anthranilic acid amide or whichanthranilic acid amides from the group of the so-called oatsavenanthramides, which contains more than 30 substances, is/are involvedin the alleviation of reddening reactions and itching.

The present invention is based on extensive studies, in particular onthe following aspects:

-   -   Structure/activity considerations for identification of        anthranilic acid amides with a reddening- and itch-alleviating        action.    -   Preparation of plant extracts with a high content of specific,        highly effective anthranilic acid amides, in particular        preparation of specific oat and carnation extract fractions, and        also of purified isolated active compounds, in particular from        oats and/or carnations.    -   Synthesis of anthranilic acid amides with an itch-alleviating        action.

The aim of the said studies was to make available particularly activecompounds in preferably highly pure form, so that they can be used inpharmaceutical or cosmetic products free from any toxicologically ordermatologically critical subsidiary constituents (synthesis by-productsor plant extract subsidiary constituents).

In general, it was to be borne in mind here that the substances to beused in cosmetic and/or pharmaceutical products should be

-   -   toxicologically acceptable,    -   well tolerated by the skin,    -   stable (in particular in the customary cosmetic and/or        pharmaceutical formulations),    -   preferably odourless and    -   able to be produced inexpensively (i.e. using standard processes        and/or starting from standard precursors)        in the concentration range relevant for activity.

Preferred embodiments of the uses according to the invention and alsocompounds according to the invention can be seen from the followingexamples and the associated tables:

1. Synthesis of Anthranilic Acid Amides of the Formula 1

EXAMPLE 1

Synthesis of cinnamoylanthranilic acid derivatives that areunsubstituted or substituted in the nucleus, takingN-(4-hydroxycinnamoyl)anthranilic acid (avenanthramide D, 10; cf. Table1a) as an example

15 g (91 mmol) 4-hydroxycinnamic acid, 50 ml acetic anhydride and 0.5 mlpyridine are stirred at room temperature for 20 h. The mixture is pouredinto ice-water and the precipitated 4-acetoxycinnamic acid is separatedoff and dried (18 g). 15 g (77 mmol) 4-acetoxycinnamic acid areinitially introduced and 15 g (100 mmol) thionyl chloride addeddropwise. The mixture is then stirred for 1 h under reflux, the excessthionyl chloride is separated off by distillation and 50 ml toluene isadded to the acid chloride. A solution of 7 g (51 mmol) anthranilic acidin 70 ml pyridine is added and the reaction mixture is stirred for 2 hat 90° C. After cooling, the reaction mixture is poured into ice-waterand extracted with ethyl acetate, the organic phase is washed with wateruntil neutral and the solvent is removed under vacuum. 300 g 10% sodiumhydroxide solution is added to the residue and the mixture is stirredunder reflux for 1-2 h. After cooling, the mixture is acidified withconcentrated hydrochloric acid and extracted with ethyl acetate and theorganic phase is washed with water until neutral and the solvent isremoved under vacuum. The crude product (23 g) is recrystallised byrepeated dissolving, with heating, in ethanol, cooling and precipitationby addition of water and is further purified by RP-18 medium-pressurechromatography (column: YMC ODS-AQ, eluent: methanol/water 50:50+0.5 mlacetic acid/I, λ 280 nm) (yield: 1.1 g 10, purity: 95%).

Spectroscopic data: ¹H-NMR (300 MHz, D₆ acetone): 8.91 (1 H, dd, J=1.2and 8.5 Hz), 8.14 (1H, dd, J=1.7 and 8.1 Hz), 7.67 (1H, d, J=15.4 Hz),7.61 (1 H, m), 7.60 (2 H, d, J=8.7 Hz), 7.16 (1 H, m), 6.92 (2 H, d,J=8.7 Hz), 6.64 (1 H, d, J=15.4 Hz).—¹³C-NMR (75.5 MHz, D₆ acetone):170.5 (s), 165.3 (s), 160.2 (s), 143.3 (s), 142.7 (d), 135.2 (d), 132.2(d), 130.8 (2C, d), 127.3 (s), 123.0 (d), 120.9 (d), 119.8 (d), 116.6(2C, d), 115.8 (s).

EXAMPLE 2

Catalytic hydrogenation of cinnamoylanthranilic acid derivatives thatare unsubstituted or unsubstituted in the nucleus to give thecorresponding dihydro compound (8, Table la) takingN-(4-hydroxycinnamoyl)-anthranilic acid (avenanthramide D, 10) as anexample.

140 mg N-(4-hydroxycinnamoyl)anthranilic acid (avenanthramide D, 10) aretaken up in 20 ml ethanol and quantitatively hydrogenated with hydrogenin the presence of palladium (5% on active charcoal).

Spectroscopic data: ¹H-NMR (300 MHz, D₆ acetone): 8.68 (1 H, dd, J=0.8and 8.4 Hz), 8.08 (1 H, dd, J=1.5 and 7.8 Hz), 7.59 (1 H, m), 7.15 (1 H,m), 7.12 (2 H, d, J=8.5 Hz), 6.77 (2 H, d, J=8.5 Hz), 2.95 (2 H, t,J=7.6 Hz), 2.75 (2 H, t, J=7.6 Hz).

2. Extraction of Anthranilic Acid Amide Fractions from Plants

EXAMPLE 3

Extraction of an anthranilic acid amide-containing extract fromcultivated oats (Avena sativa)

143 kg ethanol/water 7:3 (m/m) are added to 9 kg cultivated oats and themixture is macerated for 3 days at room temperature. After filtration,the extract is concentrated to the aqueous phase under vacuum (17.4 kg,solids content: 2.5%, Σ avenanthramides A, B & C in dry extract:0.093%).

The aqueous solution is extracted in portions (2 kg) by stirring withAmberlite XAD-16 (270 g). The adsorber resin is separated off via afrit, washed with water and eluted with methanol/water 1:1 (V/V). Thecombined eluates are freed from solvent under vacuum. Dry extract: 8.5g, Σ avenanthramides A, B & C. 1.2%.

This dry extract is taken up in ethanol/water 1:1 (V:V) and adjusted toan avenanthramide content Σ A, B & C of 500 ppm by dilution withethanol/water 1:1 (V:V).

3. Activity Studies on the Inhibition of Substance P-Induced Release ofHistamine from Mast Cells by Anthranilic Acid Amides of the GeneralFormula 1.

3.1. Synthetic Anthranilic Acid Amides

Test Products

Stock solutions: avenanthramides 2 to 19 (structural formulae: see Table1a) and dianthramides 20-29 (structural formulae: see Table 1b);concentration: 1% in ethanol; storage before use at 4° C.)

Reagents

Substance P: BACHEM.

Test Design:

Mast cells from the peritoneal tissue of rats were isolated bycentrifuging on metrizamide and stimulated with substance P (10 μM).Calcium chloride served as positive control.

Sample Preparation: Test and Reference Substances:

The synthetically prepared avenanthramides and dianthramides of theFormulae 2 to 29 (cf. Tables 1a/1b) were diluted with buffer medium tothe final concentrations (0.5; 5 and 50 ppm, see Tables 1a/1b),corresponding to an ethanol concentration of 0.5; 0.05 and 0.005% (V/V),respectively. Calcium chloride, which served as positive control, waslikewise diluted with buffer medium so that solutions in theconcentration range from 10⁻⁸ to 10⁻² M were available.

Incubation Protocol:

Test system: The final test solutions were incubated for 2 minutes inthe presence of substance P and of the reference substance (CaCl₂) or ofthe particular sample to be tested (incubation temperature: 37° C.).Cells that had been incubated in the absence of substance P andreference or sample substance served as blank.

Determination of the Total Histamine Content After Cell Lysis:

The reaction solutions were first freed from cell constituents bycentrifuging. The histamine present in the supernatant liquor was thenconverted to a derivative with OPT and the fluorescence of the solutionswas determined photometrically (fluorometer Cytofluor 2350).

Result:

Calcium chloride inhibited substance P-induced release of histamine frommast cells depending on the concentration. It was possible to achieve50% inhibition with a calcium chloride concentration of 639 μM. Thiscorresponds to the value to be expected and thus validates thefundamental test design.

The values for the various avenanthramides and dianthramides are givenin Table 1a/1b as % inhibition based on the histamine content of cellsstimulated with substance P.

3.2.Anthranilic Acid Amide Fraction from Oat Seeds in Direct Comparisonwith a Reconstituted Product Consisting of Identical Mass Ratios ofSynthetically Prepared Oat Anthranilic Acid Amides

Test Products

Stock solutions: GS-101100-A and GS-101100-B (composition of thesamples: see Table 2; concentration: 500 ppm E avenanthramides A, B andC in glycerol; storage before use at 4° C.)

Reagents

Substance P: BACHEM.

Test Design:

Mast cells from the peritoneal tissue of rats were isolated bycentrifuging on metrizamide and stimulated with substance P (10 μM).Calcium chloride served as positive control.

Sample Preparation: Test and Reference Substances:

The GS-101100-A and GS-101100-B samples were diluted with buffer mediumto the final concentrations (0.5; 5 and 50 ppm, see Table 2),corresponding to an ethanol concentration of 0.1; 1 and 10% (V/V)respectively. Calcium chloride, which served as positive control, waslikewise diluted with buffer medium so that solutions in theconcentration range from 10⁻⁵ and (sic) 10⁻² M were available.

Incubation Protocol:

Test system: The final test solutions were incubated for 2 minutes inthe presence of substance P and of the reference substance (CaCl₂) or ofthe particular sample to be tested (incubation temperature: 37° C.).Cells that had been incubated in the absence of substance P andreference or sample substance served as blank.

Determination of the Total Histamine Content after Cell Lysis:

The reaction solutions were first freed from cell constituents bycentrifuging. The histamine present in the supernatant liquor was thenconverted to a derivative with OPT and the fluorescence of the solutionswas determined photometrically (fluorometer Cytofluor 2350).

Result:

Calcium chloride inhibited substance P-induced release of histamine frommast cells depending on the concentration. Within this test series, itwas possible to obtain a 50% inhibition at a calcium chlorideconcentration of 432 μM. This corresponds to the value to be expectedand thus validates the fundamental test design.

The values for the various avenanthramides are given in Table 2 as %inhibition based on the histamine content of cells stimulated withsubstance P without the addition of inhibitors.

4. Results and Structure/Activity Considerations

4.1. Synthetic Anthranilic Acid Amides

Results of tests on selected, highly pure anthranilic acid amides withcinnamic acid partial structure and dihydrocinnamic acid partialstructure (avenanthramides) show that there are significant differencesin the activity depending on the substitution sample. The highestactivity, i.e. complete inhibition of the histamine release, is achievedwith substances of the Formulae 2 and 3 (cf. Table 1a), which havevicinal hydroxyl groups in the 3- and 4-positions of the cinnamicacids/dihydrocinnamic acid part. On the other hand, further hydroxylgroups in the anthranilic acid part do not lead to an additionalincrease in activity here. This is shown by the virtually identicalinhibition data for substance 2 (7%, 80% and 108% for an activesubstance concentration of 0.5, 5 and 50 ppm, respectively, cf. Table1a) and substance 3 (11%, 62% and 106% for an active substanceconcentration of 0.5; 5 and 50 ppm, respectively, cf. Table 1a). Thus,an inhibition of the histamine release of >50% can already be achievedwith a dosage of 5 ppm, whereas, on the other hand, tranilast (substance15, Table 1a) is capable of only 21% inhibition of the histamine releaseunder identical test conditions, even in the highest dosage of 50 ppm.

An activity significantly higher than that of tranilast is also observedin the case of anthranilic acid amides with only one free hydroxyl groupin the cinnamic acid/dihydrocinnamic acid part, and specificallyespecially when this is arranged in the 4-position of the cinnamicacid/dihydrocinnamic acid part constituent (Table 1a: substances 4-10).The percentage rate of histamine release inhibition for a dosage of 50ppm is in the range of 37-49% here. Here again, additional substituentsin the anthranilic acid part do not lead to any significant increase inactivity. Thus, within the group of anthranilic acid amides with onlyone free hydroxyl group in the cinnamic acid/dihydrocinnamic acid partas well, there is a distinctly higher activity in direct comparison withtranilast.

An activity higher than that of tranilast is also observed withanthranilic acid amides with only one free hydroxyl group in theanthranilic acid residue, and specifically especially when this is inthe 4-position of the anthranilic acid residue (cf. Table 1: substances11-13). The percentage rate of the histamine release inhibition at adosage of 50 ppm is in the range of 30-36% here.

The substances 2-13 are illustrative representatives of a preferredsub-group of compounds of the Formula 1, for which:

n=1 and

furthermore:

m=1, 2 or 3,

with the proviso that X has been selected at least once from the groupthat consists of OH or (sic) Oacyl.

and/or

p=1 or2,

with the proviso that Y has been selected at least once from the groupthat consists of OH and Oacyl.

Substances 14-19, which also include tranilast (substance 15), exert aninhibitory effect in respect of histamine release that is no longersatisfactory, compared with the substances designated above.

The comparatively low activity of tranilast agrees with the researchcarried out by Hachisuka et al. (Arch Dermatol Res Vol. 280, p. 158-162;1988). The authors were able to establish a 50% inhibition of thehistamine release only at a concentration of 327 ppm. Apparently, thealkylation of the vicinal hydroxyl groups in the cinnamic acid part ordihydrocinnamic acid part is accompanied by a significant reduction inactivity.

Corresponding structure/activity considerations within the group ofcompounds with a benzoic acid partial structure (dianthramides) led tocomparable results. Here the compounds with two vicinal hydroxyl groupsin the 3- and 4-positions of the benzoic acid residue (cf. Table 1b; cf.in particular substance 20) have the greatest activity. Dianthramideswith at least one free hydroxyl group in the benzoic acid part of themolecule also show an activity that, although it is slightly weaker, isnevertheless good.

Compounds 20-29 listed in Table 1b are illustrative representatives of apreferred sub-group of compounds of the Formula 1, for which n=0.

4.2 Anthranilic Acid Amide Fractions of Vegetable Origin

In addition to synthetically prepared avenanthramides and dianthramides,various plant extracts were also studied with regard to the suitabilitythereof for the inhibition of substance P-induced release of histaminefrom mast cells. Table 2 shows, by way of example, the results of thedirect comparison of an oat extract (cf. Table 2: sample GS10100-A, oatextract standardised to 500 ppm Σ avenanthramides 3, 4 and 5; formulae:cf. also Table 1a;) and a synthetic reconstituted product containing atotal of 500 ppm Σ synthetic avenanthramides 3, 4 and 5 (sampleGS10100-B, cf. also Table 1a) in precisely comparable mass ratios.

The direct comparison of the two samples proves that the inhibition ofthe substance P-induced release of histamine from mast cells isessentially caused by the avenanthramides 3, 4 and 5 contained in oatextract (cf. Table 1a).

This finding shows, in general, that, in addition to synthetic compoundsaccording to the invention, plant extracts and fractions preparedtherefrom that contain these substances in a standardised amount canalso preferentially be used as inhibitors of the substance P-inducedrelease of histamine from mast cells and thus are able to preventinflammation, reddening and itching reactions and/or to contribute toalleviating these.

5. Review of Selected Substances Already Known and Not Known Hithertofor Use as Histamine Release Inhibitors:

In Tables 3 and 4, on the one hand, substances not known hitherto and,on the other hand, substances already known that are preferably used ashistamine release inhibitors are listed by way of example. Substances2-29 are already in Tables 1 a and 1b; substances 30-80 are not in thesetables.

The substances contained in Tables 3 and 4 are all acids; however, it ispointed out that the corresponding esters (where R³=alkyl instead ofR³═H) and the corresponding pharmaceutically acceptable salts can alsobe used in the same way.

6. Summary of the Test Results and Supplementary Remarks:

The tests carried out show, surprisingly, that the compounds of theFormula 1 according to the invention inhibit the substance P-inducedrelease of histamine from mast cells in a use concentration that isconsiderably lower compared with tranilast and thus, because of thelower therapeutic use concentration and the lower toxicological riskpotential associated therewith, can preferably be used as activecompounds. The compounds and mixtures that can be used according to theinvention can be highly pure synthesis products, pure isolated productsfrom plant extracts, such as, for example, from oats (Avena sativa) orcarnation species (Dianthus spec.) or specific extract fractions fromplants such as oats (Avena sativa) or carnations (Dianthus sp.), whichcontain the compounds according to the invention, which are preferablyto be used, in high concentration.

Instead of the compounds tested, compounds (precursors) in which thehydroxyl groups in the cinnamic acid/dihydrocinnamic acid part or in thebenzoic acid part have been acylated, can preferably also be used (X orY=Oacyl where acyl=CO—R where R=—CH₃, or a straight-chain or branchedalkyl radical with 2-30 C atoms). In addition, precursors in which thecarboxyl groups in the anthranilic acid part have been alkylated (whereR³=—CH₃, or straight-chain or branched alkyl radicals with chain lengthsC 2 to 30) can preferably also be used. On topical application,corresponding acylated or alkylated compounds of the Formula 1 penetratevery well into deeper layers of the skin. Here they are cleaved by thenon-specific esterases endogenously present in human and animal skin, sothat the actual active principle is released only at the site of action.

Depending on the substance, the use concentration of the compounds ofthe Formula 1 that can be used according to the invention is in theconcentration range of 0.0001 to 10% (m/m) and preferably in theconcentration range of 0.001-1% (m/m), based on the total mass of acosmetic or pharmaceutical end product ready for use.

The histamine release inhibitors, and in particular those of theavenanthramide and dianthramide type, used according to the inventioncan be incorporated without difficulty in conventional cosmetic ordermatological/keratological formulations such as, inter alia, pumpsprays, aerosol sprays, creams, shampoos, ointments, tinctures, lotions,nail care products (for example nail varnishes, nail varnish removers,nail balsams) and the like. In this context it is also possible, and insome cases advantageous, to combine the histamine release inhibitorsaccording to the invention with further active compounds, for examplewith other, optionally even synergistically intensifying, histaminerelease inhibitors or with anti-inflammatory substances and/orsubstances that reduce itching and reddening, the action of which isbased on a different principle of action, such as, for example, theinhibition of the release of inflammation mediators (inter alialeucotrienes, prostaglandins or cytokins (sic)). In this context thecosmetic and/or dermato-logical/keratological formulations containingthe histamine release inhibitors according to the invention canotherwise be of customary composition and serve for treatment of theskin and/or the hair in the sense of a dermatological or keratologicaltreatment or of a treatment in the sense of care cosmetics. However,they can also be used in make-up products in decorative cosmetics.

Cosmetic formulations that contain the histamine release inhibitorsaccording to the invention can also contain further anti-inflammatoryactive compounds or active compounds having a reddening- anditch-alleviating action. In this context all anti-inflammatory activecompounds and active compounds that alleviate reddening and itching thatare suitable or customary for cosmetic and/or dermatologicalapplications can be used. Advantageously, the anti-inflammatory activecompounds and active compounds alleviating reddening and/or itching thatare used are steroidal anti-inflammatory substances of thecorticosteroid type, such as, for example, hydrocortisone,dexamethasone, dexamethasone phosphate, methylprednisolone or cortisone,it being possible to expand the list by adding further steroidalanti-inflammatory agents. Non-steroidal anti-inflammatory agents canalso be used. Oxicams, such as piroxicam or tenoxicam; salicylates, suchas aspirin, Disalcid, Solprin or fendosal; acetic acid derivatives, suchas diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, orclindanac; fenamates, such as mefenamic, meclofenamic, flufenamic orniflumic; propionic acid derivatives, such as ibuprofen, naproxen,benoxaprofen or pyrazoles, such as phenylbutazone, oxyphenylbutazone,febrazone or azapropa-zone, may be mentioned here by way of example.Alternatively, natural anti-inflammatory substances and substances thatalleviate reddening and/or itching can be used. Plant extracts, specialhighly active plant extract fractions and also highly pure activesubstances isolated from plant extracts can be used. Extracts, fractionsand active substances from camomile, aloe vera, Commiphora species,Rubia species, willows, willow-herb and pure substances such as, interalia, bisabolol, apigenin-7-glucoside, boswellic acid, phytosterols,glycyrrhizine, glabridin or licochalkon A are particularly preferred.The formulations containing histamine release inhibitors can alsocontain mixtures of 2 or more anti-inflammatory active compounds.

Cosmetic formulations that contain histamine release inhibitorsaccording to the invention can also contain active compounds forpreservation, it being possible to use all preservatives that aresuitable or customary for cosmetic and/or dermatological applications.Advantageously, preservatives such as, inter alia, benzoic acid, theesters and salts thereof, propionic acid and salts thereof, salicylicacid and salts thereof, 2,4-hexanoic acid (sorbic acid) and saltsthereof, formaldehyde and paraformaldehyde, 2-hydroxybiphenyl ether andsalts thereof, 2-zincsulphidopyridine-N-oxide, inorganic sulphites andbisulphites, sodium iodate, chlorobutanolum, 4-hydroxybenzoic acid, thesalts and esters thereof, dehydratcetic (sic) acid, formic acid,1,6-bis(4-amidino-2-bromophenoxy)-n-hexane and salts thereof, the sodiumsalt of ethylmercury-(II)-thiosalicylic acid, phenylmercury and saltsthereof, 10-undecylenic acid and salts thereof,5-amino-1,3-bis(2-ethylhexyl)-5-methylhexahydropyrimidine,5-bromo-5-nitro-1,3-dioxane, 2-bromo-2-nitro-1,3-propanediol,2,4-dichlorobenzyl alcohol,N-(4-chlorophenyl)-N′-(3,4-dichlorophenyl)urea, 4-chloro-m-cresol,2,4,4′-trichloro-2′-hydroxy-diphenyl ether, 4-chloro-3,5-dimethylphenol,1,1′-methylene-bis(3-(1-hydroxymethyl-2,4-dioximidazolidin-5-yl)urea),poly-(hexamethylene diguanide) hydrochloride, 2-phenoxyethanol,hexamethylentetramine,1-(3-chloroallyl)-3,5,7-triaza-1-azonia-adamantane chloride, 1(4-chloro-phenoxy)-1(1H-imidazol-1-yl)-3,3-dimethyl-2-butanone,1,3-bis-(hydroxy-methyl)-5,5-dimethyl-2,4-imidazolidinedione, benzylalcohol, Octopirox, 1,2-dibromo-2,4-dicyanobutane,2,2′-methylene-bis(6-bromo-4-chloro-phenol), bromochlorophene, mixtureof 5-chloro-2-methyl-3(2H)-isothiazolinone and2-methyl-3(2H)isothiazlinone (sic) with magnesium chloride and magnesiumnitrate, 2-benzyl-4-chlorophenol, 2-chloracetamide, chlorhexidine,chlorhexidine acetate, chlorhexidine gluconate, chlorhexidinehydrochloride, 1-phenoxy-propan-2-ol, N-alkyl(C₁₂-C₂₂)trimethylammoniumbromide and chloride, 4,4-dimethyl-1,3-oxazolidine,N-hydroxymethyl-N-(1,3-di(hydroxymethyl)-2,5-dioxo-imidazolidin-4-yl)-N′-hydroxymethylurea,1,6-bis(4-amidino-phenoxy)-n-hexane and salts thereof, glutaraldehyde5-ethyl-1-aza-3,7-dioxa-bicyclo(3.3.0)octane,3-(4-chlorphenoxy)-1,2-propanediol, hyamine,alkyl-(C₈-C₁₈)-dimethylbenzylammonium chloride,alkyl-(C₈-C₁₈)-dimethylbenzylammonium bromide,alkyl-(C₈-C₁₈)-dimethyl-benzyl-ammonium saccharinate, benzylhemiformal,3-iodo-2-propinylbutyl carbamate, sodium hydroxymethylaminoacetate orsodium hydroxy-methylaminoacetate (sic) are chosen.

Further antibacterial or antimycotic active substances can also be usedparticularly advantageously in the cosmetic formulations that containhistamine release inhibitors according to the invention, it beingpossible to use all antibacterial or antimycotic active substances thatare suitable or customary for cosmetic and/or dermatologicalapplications. In addition to the large group of conventionalantibiotics, in particular the products relevant for cosmetics, such astriclosan, climbazol, octoxyglycerol, Octopirox(1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone,2-aminoethanol), chitosan, farnesol, glycerol monolaurate orcombinations of the said substances, which, inter alia, are used againstunderarm odour, foot odour or dandruff, are advantageous here.

In addition, the synergistic mixtures of histamine release inhibitorsaccording to the invention can also be used particularly advantageouslyin combination with perspiration-inhibiting active compounds(antiperspirants) for controlling body odour. Perspiration-inhibitingactive compounds used are, in particular, aluminium salts, such asaluminium chloride, aluminium chlorohydrate, nitrate, sulphate, acetateetc. In addition, however, the use of zinc, magnesium and zirconiumcompounds can also be advantageous. Essentially the aluminium saltsand—to a somewhat lesser extent—aluminium/zirconium salt combinationshave proved their worth for use in cosmetic and dermatologicalantiperspirants. The partially neutralised aluminium hydroxychlorides,which are thus better tolerated by the skin but are not quite aseffective, are also worthy of mention. In addition to aluminium salts,further substances can also be used, such as, for example, a)protein-precipitating substances such as, inter alia, formaldehyde,glutaraldehyde, natural and synthetic tanning agents and alsotrichloroacetic acid, which give rise to surface closure of the sweatglands, b) local anaesthetics (inter alia dilute solutions of, forexample, lidocaine, prilocaine or mixtures of such substances) thatswitch off the sympathetic supply of the sweat glands by blocking theperipheral nerve paths, c) zeolites of the X, A or Y type, which inaddition to reducing sweat secretion also act as adsorbents for badodours, and d) botulinus toxin (toxin of the bacterium Chlostridiumbotulinum), which is also used in the case of hyperhidrosis, apathologically increased sweat secretion, and the action of which isbased on an irreversible blockage of the release of the transmittersubstance acetylcholine relevant for sweat secretion.

A combination with (metal) chelating agents can also be advantageous inthe cosmetic formulations that contain histamine release inhibitorsaccording to the invention, it being possible to use all metal chelatingagents that are suitable or customary for cosmetic and/or dermatologicalapplications. (Metal) chelating agents that are preferably to be usedare, inter alia, α-hydroxy fatty acids, phytic acid, lactoferrin,α-hydroxy acids, such as, inter alia, citric acid, lactic acid and malicacid, as well as humic acids, bile acids, bile extracts, bilirubin,biliverdin or EDTA, EGTA and derivatives thereof.

For use, the formulations containing histamine release inhibitorsaccording to the invention are applied to the skin and/or the hair in anadequate amount in the manner customary for cosmetics and dermatologicalproducts. In this context cosmetic and dermatological formulations thatcontain a mixture according to the invention and additionally act as asunscreen offer particular advantages. Advantageously, theseformulations contain at least one UVA filter and/or at least one UVBfilter and/or at least one inorganic pigment. In this context theformulations can be in various forms, such as are, for example,customarily employed for this type of formulation. Thus, they can be,for example, a solution, an emulsion of the water-in-oil (W/O) type orof the oil-in-water (O/W) type or a multiple emulsion, for example ofthe water-in-oil-in-water (W/O/W) type, a gel, a hydrodispersion, asolid stick or also an aerosol.

As mentioned, formulations that contain histamine release inhibitorsaccording to the invention can advantageously be combined withsubstances that absorb UV radiation in the UVB range, the total amountof the filter substances being, for example, 0.01% (mlm) to 40% (m/m),preferably 0.1% to 10% (mlm), in particular 1.0 to 5.0% (m/m), based onthe total weight of the formulations, in order to make availablecosmetic formulations that protect the hair and/or the skin against theentire range of ultraviolet radiation. They can also serve as sunscreensfor hair. If the formulations according to the invention contain UVBfilter substances, these can be oil-soluble or water-soluble.Advantageous oil-soluble UVB filters are, for example:3-benzylidenecamphor derivatives, preferably3-(4-methylbenzylidene)camphor, 3-benzylidenecamphor; 4-aminobenzoicacid derivatives, preferably 2-ethylhexyl 4-(dimethyl-amino)benzoate,amyl 4-(dimethylamino)benzoate, esters of cinnamic acid, preferably2-ethylhexyl 4-methoxycinnamate, isopentyl 4-methoxy-cinnamate; estersof salicylic acid, preferably 2-ethylhexyl salicylate, 4-isopropylbenzylsalicylate, homomenthyl salicylate, derivatives of benzophenone,preferably 2-hydroxy-4-methoxybenzophenone,2-hydroxy-4-methoxy-4′-methylbenzophenone,2,2′-dihydroxy-4-methoxy-benzophenone, esters of benzalmalonic acid,preferably di(2-ethylhexyl)4-methoxybenzalmalonate,2,4,6-trianilino-(p-carbo-2′-ethyl-1′-hexyloxy)-1,3,5-triazine.Advantageous water-soluble UVB filters are, for example, salts of2-phenylbenzimidazole-5-sulphonic acid, such as the sodium, potassium ortriethanolammonium salt thereof, and also the sulphonic acid itself;sulphonic acid derivatives of benzophenones, preferably2-hydroxy-4-methoxybenzophenone-5-sulphonic acid and salts thereof;sulphonic acid derivatives of 3-benzylidenecamphor, such as, forexample, 4-(2-oxo-3-bomylidenemethyl)benzenesulphonic acid,2-methyl-5-(2-oxo-3-bomylidene-methyl)sulphonic acid and salts thereofand also 1,4-di(2-oxo-10-sulpho-3-bomylidenemethyl)-benzene and saltsthereof (the corresponding 10-sulphato compounds, for example thecorresponding sodium, potassium or triethanolammonium salt) and alsobenzene-1,4-di(2-oxo-3-bomylidenemethyl-10-sulphonic acid (sic).

The above list of the said UVB filters that can be used in combinationwith the histamine release inhibitors according to the invention should,of course, not be understood as definitive. It can also be advantageousto employ UVA filters, such as are customarily contained in cosmeticformulations. These substances are preferably derivatives ofdibenzoylmethane, in particular1-(4′-tert.-butylphenyl)-3-(4′-methoxy-phenyl)propane-1,3-dione and1-phenyl-3-(4′-isopropylphenyl)propane-1,3-dione. The amounts used forthe UVB combination can be used.

In cosmetic formulations, the histamine release inhibitors according tothe invention can advantageously also be combined with further cosmeticauxiliaries, such as are customarily used in such formulations, thus,for example, with antioxidants, perfume oils, agents to prevent foaming,colorants, pigments that have a colouring action, thickeners,surface-active substances, emulsifiers, plasticising substances,moistening and/or moisture-retaining substances, fats, oils, waxes orother conventional constituents of a cosmetic formulation, such asalcohols, polyols, polymers, foam stabilisers, electrolytes, organicsolvents or silicone derivatives. According to the invention allconceivable antioxidants, perfume oils, agents to prevent foaming,colorants, pigments that have a colouring action, thickeners,surface-active substances, emulsifiers, plasticising substances,moistening and/or moisture-retaining substances, fats, oils, waxes,alcohols, polyols, polymers, foam stabilisers, electrolytes, organicsolvents or silicone derivatives that are suitable or customary forcosmetic and/or dermatological applications can be used here.

A high content of treatment substances is usually advantageous informulations containing histamine release inhibitors according to theinvention for the topical prophylactic or cosmetic treatment of theskin. According to a preferred embodiment, the compositions contain oneor more animal and/or vegetable treatment fats and oils, such as oliveoil, sunflower oil, purified soya oil, palm oil, sesame oil, rapeseedoil, almond oil, borage oil, evening primrose oil, coconut oil, sheabutter, jojoba oil, sperm oil, beef tallow, neatsfoot oil and lard, andalso optionally further treatment constituents, such as, for example,fatty alcohols having 8-30 C atoms. The fatty alcohols used here can besaturated or unsaturated and straight-chain or branched. For example,decanol, decenol, octanol, octenol, dodecanol, dodecenol, octadienol,decadienol, dodecadienol, oleyl alcohol, ricinol (sic) alcohol, erucicalcohol, stearyl alcohol, isostearyl alcohol, cetyl alcohol, laurylalcohol, myristyl alcohol, arachidyl alcohol, capryl alcohol, capricalcohol, linoleyl alcohol, linolenyl alcohol and behenyl alcohol, aswell the guerbet alcohols thereof, can be used, in which context itwould be possible to extend this list arbitrarily by furtherstructurally chemically related alcohols. The fatty alcohols preferablyoriginate from natural fatty acids, and are usually prepared from thecorresponding esters of the fatty acids by reduction. Furthermore, fattyalcohol fractions that are formed from naturally occurring fats and fatoils by reduction can be used, such as, for example, beef tallow, peanutoil, colza oil, cottonseed oil, soya oil, sunflower oil, palm kerneloil, linseed oil, maize oil, castor oil, rapeseed oil, sesame oil, cocoabutter and cocoa fat.

In addition, the treatment substances that can preferably be combinedwith the histamine release inhibitors according to the invention alsoinclude

-   -   ceramides, ceramides being understood to be N-acylsphingosines        (fatty acid amides of sphingosine) or synthetic analogues of        such lipids (so-called pseudo-ceramides), which clearly improve        the water retention capacity of the stratum corneum.    -   phospholipids, for example soya lecithin, egg lecithin and        cephalins    -   Vaseline, paraffin and silicone oils; the latter include, inter        alia, dialkyl- and alkylaryl-siloxanes, such as        dimethylpolysiloxane and methylphenylpolysiloxane, as well as        the alkoxylated and quaternised derivatives thereof.

Animal and/or vegetable hydrolysed proteins can advantageously also beadded to the formulations containing the histamine release inhibitorsaccording to the invention. In this regard, in particular elastin,collagen, keratin, lactoprotein, soya protein, oat protein, pea protein,almond protein and wheat protein fractions or corresponding hydrolysedproteins, but also the condensation products thereof with fatty acids,and also quaternised hydrolysed proteins are advantageous, the use ofvegetable hydrolysed proteins being preferred.

Insofar as a cosmetic or dermatological formulation containing thehistamine release inhibitors according to the invention is a solution orlotion, the solvents used can be:

-   -   water or aqueous solutions;    -   fatty oils, fats, waxes and other natural and synthetic fatty        bodies, preferably esters of fatty acids with alcohols having a        low C number, for example with isopropanol, propylene glycol or        glycerol, or esters of fatty alcohols with alkanoic acids having        a low C number or with fatty acids;    -   alcohols, diols or polyols having a low C number, as well as the        ethers thereof, preferably ethanol, isopropanol, propylene        glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or        monobutyl ether, propylene glycol monomethyl, monoethyl or        monobutyl ether, diethylene glycol monomethyl or monoethyl ether        and analogous products.

In particular, mixtures of the abovementioned solvents are used. In thecase of alcoholic solvents, water can be a further constituent.

Cosmetic formulations that contain histamine release inhibitorsaccording to the invention can also contain antioxidants, it beingpossible to use all antioxidants suitable or customary for cosmeticand/or dermatological applications. Advantageously, the antioxidants areselected from the group consisting of amino acids (for example glycine,histidine, tyrosine, tryptophan) and the derivatives thereof, imidazoles(for example urocanic acid) and the derivatives thereof, peptides suchas D, L-carnosine, D-carnosine, L-carnosine and the derivatives thereof(for example anserine), carotinoids, carotenes (for example α-carotene,β-carotene, lycopene) and the derivatives thereof, lipoic acid and thederivatives thereof (for example dihydrolipoic acid), aurothioglucose,propylthiouracil and other thiols (for example thioredoxin, glutathione,cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl,propyl, amyl, butyl and lauryl, palmitoyl, oleyl, γ-linoleyl,cholesteryl and glyceryl esters thereof) as well as the salts thereof,dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionicacid and the derivatives thereof (esters, ethers, peptides, lipids,nucleotides, nucleosides and salts) and also sulphoximine compounds (forexample buthionine sulphoximines, homocysteine sulphoximine, buthioninesulphones, penta-, hexa-, hepta-thionine suphoximine) in very lowtolerated doses, and also (metal) chelating agents, for exampleα-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin,α-hydroxy acids (for example citric acid, lactic acid, malic acid),humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTAand the derivatives thereof, unsaturated fatty acids and the derivativesthereof (for example γ-linolenic acid, linoleic acid, oleic acid), folicacid and the derivatives thereof, ubiquinone and ubiquinol and thederivatives thereof, Vitamin C and derivatives (for example ascorbylpalmitate, Mg ascorbyl phosphate, ascorbyl acetate), tocopherols and thederivatives thereof (for example Vitamin E acetate), Vitamin A and thederivatives thereof (Vitamin A palmitate) and also coniferyl benzoate ofbenzoin resin, rutinic acid and the derivatives thereof, ferrulic acidand the derivatives thereof, butylhydroxytoluene, butylhydroxyanisole,nordihydroguaiacic acid, nordihydroguaiaretic acid,trihydroxybutyrophenone, uric acid and the derivatives thereof, mannoseand the derivatives thereof, zinc and the derivatives thereof (forexample ZnO, ZnSO4 (sic)), selenium and the derivatives thereof (forexample selenium methionine), stilbenes and the derivatives thereof (forexample stilbene oxide, trans-stilbene oxide) and the derivatives(salts, esters, ethers, sugars, nucleotides, nucleosides, peptides andlipids) of the said active compounds that are suitable according to theinvention.

Cosmetic formulations that contain histamine release inhibitorsaccording to the invention can also contain vitamins and vitaminprecursors, it being possible to use all vitamins and vitamin precursorssuitable or customary for cosmetic and/or dermatological applications.Mention may be made here in particular of vitamins and vitaminprecursors such as tocopherols, Vitamin A, nicotinic acid andnicotinomide, further vitamins of the B complex, in particular biotin,and Vitamin C. Furthermore, within this group pantothenyl alcohol andthe derivatives thereof, in particular esters and ethers of pantothenylalcohol, and also derivatives of pantothenyl alcohols obtainedcationically, such as, for example, pantothenyl alcohol triacetate,pantothenyl alcohol, monoethyl ether and the monoacetate thereof andalso cationic pantothenyl alcohol derivatives are preferably used.

Cosmetic formulations that contain histamine release inhibitorsaccording to the invention can also contain active compounds having askin lightening action. In this context all skin lightening activecompounds that are suitable or customary for cosmetic and/ordermatological applications can be used according to the invention.Advantageous skin lightening active compounds are, to this extent, kojicacid, hydroquinone, arbutin, ascorbic acid, magnesium ascorbylphosphate,liquorice root extracts and the constituents thereof glabridin orlicochalkon A, or extracts from Rumex and Ramulus species, extracts frompine species (Pinus) or extracts from Vitis species which contain, interalia, skin-lightening stilbene derivatives.

Cosmetic formulations that contain histamine release inhibitorsaccording to the invention can also contain active compounds having askin-tanning action. To this extent all skin-tanning active compoundsthat are suitable or customary for cosmetic and/or dermatologicalapplications can be used. Dihydroxyacetone (DHA;1,3-dihydroxy-2-propanone) may be mentioned here by way of example. DHAcan be either in monomer or in dimer form, the proportion of dimersbeing predominant in the crystalline form.

Cosmetic formulations that contain histamine release inhibitorsaccording to the invention can also contain mono-, di- andoligo-saccharides, such as, for example, glucose, galactose, fructose,mannose, fructose (sic) and lactose.

Cosmetic formulations that contain histamine release inhibitorsaccording to the invention can also contain plant extracts, which areusually prepared by extraction of the complete plant, but in individualcases are also prepared exclusively from blossom and/or leaves, wood,bark or roots of the plant. With regard to the plant extracts that canbe used according to the invention, reference is made in particular tothe extracts that are listed in the table starting on page 44 of thethird edition of the Leiffaden zur Inhaltsstoffdeklaration kosmetischerMittel (Guide to the Declaration of Constituents of Cosmetic Agents),published by the Industrieverband Körperpflegemittel und Waschmittele.V. (IKW), Frankfurt. The extracts from aloe, Hamamelis, algae, oakbark, willow-herb, stinging nettles, dead nettles, hops, camomile,milfoil, arnica, calendula, burdock root, horse-tail, hawthorn, lindenblossom, almonds, pine needles, horse chestnut, sandalwood, juniper,coconut, mango, apricot, orange, lemon, lime, grapefruit, apple, greentea, grapefruit seed, wheat, oats, barley, sage, thyme, basil, rosemary,birch, mallow, bitter-crass, willow bark, restharrow, coltsfoot,althaea, ginseng and ginger root are particularly advantageous. Amongstthese, the extracts from aloe vera, camomile, algae, rosemary,calendula, ginseng, cucumber, sage, stinging nettles, linden blossom,arnica and Hamamelis are particularly preferred. Mixtures of two or moreplant extracts can also be employed. Extraction agents that can be usedfor the preparation of the said plant extracts can be, inter alia,water, alcohols and mixtures thereof. Amongst the alcohols, loweralcohols, such as ethanol and isopropanol, but also polyhydric alcohols,such as ethylene glycol, propylene glycol and butylene glycol arepreferred in this context, and specifically both as sole extractingagent and also in mixtures with water. The plant extracts can be usedaccording to the invention in the pure form or also in dilute form.

Cosmetic formulations that contain histamine release inhibitorsaccording to the invention can also contain anionic, cationic, non-ionicand/or amphoteric surfactants, especially if crystalline ormicrocrystalline solids, for example inorganic micropigments, are to beincorporated into the formulations according to the invention.Surfactants are amphiphilic substances that are able to dissolveorganic, non-polar substances in water. In this context the hydrophilicparts of a surfactant molecule are usually polar functional groups, forexample, —COO⁻, —OoSO₃ ²⁻, —SO₃ ⁻, whilst the hydrophobic parts are, asa rule, non-polar hydrocarbon radicals. Surfactants are generallyclassified according to the nature and charge of the hydrophilic part ofthe molecule. Four groups can be differentiated here:

anionic surfactants,

cationic surfactants,

amphoteric surfactants and

non-ionic surfactants.

Anionic surfactants usually contain carboxylate, sulphate or sulphonategroups as functional groups. In aqueous solution they form negativelycharged organic ions in the acid or neutral medium. Cationic surfactantsare characterised virtually exclusively by the presence of a quaternaryammonium group. In aqueous solution they form positively charged organicions in the acid or neutral medium. Amphoteric surfactants contain bothanionic and cationic groups and accordingly behave like anionic orcationic surfactants in aqueous solution, depending on the pH value.They have a positive charge in a strongly acid medium and a negativecharge in an alkaline medium. In the neutral pH range, on the otherhand, they are zwitter ionic. Polyether chains are typical of non-ionicsurfactants. Non-ionic surfactants do not form ions in an aqueousmedium.

A. Anionic Surfactants

Anionic surfactants that can advantageously be used are acylamino acids(and the salts thereof), such as

-   -   acylglutamates, for example sodium acylgultamate,        di-TEA-palmitoyl aspartate and sodium capryl/caprin glutamate,    -   acylpeptides, for example palmitoyl-hydrolysed lactoprotein,        sodium cocoyl-hydrolysed soya protein and sodium/potassium        cocoyl-hydrolysed collagen,    -   sarcosinates, for example myristoyl sarcosine, TEA lauroyl        sarcosinate, sodium lauroyl sarcosinate and sodium cocoyl        sarcosinate,    -   taurates, for example sodium lauroyl taurate and sodium        methylcocoyl taurate,    -   acyl lactylates, lauroyl lactylate, caproyl lactylate    -   alaninates        carboxylic acids and derivatives, such as,    -   for example, lauric acid, aluminium stearate, magnesium        alkanolate and zinc undecylenate,    -   ester-carboxylic acids, for example calcium stearoyl lactylate,        laureth-6 citrate and sodium PEG-4 lauramidocarboxylate,    -   ether-carboxylic acids, for example sodium laureth-13        carboxylate and sodium PEG-6 cocamide carboxylate,        phosphoric acid esters and salts, such as, for example,        DEA-oleth-10 phosphate and dilaureth-4 phosphate,        sulphonic acids and salts, such as    -   acyl isothionates, for example sodium/ammonium        cocoyl-isethionate,    -   alkylarylsulphonates,    -   alkylsulphonates, for example sodium coconut monoglyceride        sulphate, sodium C₁₂₋₁₄ olefin-sulphonate, sodium lauryl        sulpho-acetate and magnesium PEG-3 cocamidosulphate,    -   sulphosuccinates, for example dioctylsodium sulphosuccinate,        disodium laureth-sulphosuccinate, disodium laurylsulphosuccinate        and disodium undecylenamido MEA-sulphosuccinate        and        sulphuric acid esters, such as    -   alkyl ether sulphate, for example sodium, ammonium, magnesium,        MIPA, TIPA laureth sulphate, sodium myreth sulphate and sodium        C12-13 pareth sulphate,    -   alkyl sulphates, for example sodium, ammonium and TEA lauryl        sulphate.        B. Cationic Surfactants

Cationic surfactants that can advantageously be used are

-   -   alkylamines,    -   alkylimidazoles,    -   ethoxylated amines and    -   quaternary surfactants.        RNH₂CH₂CH₂COO⁻ (at pH=7)        RNHCH₂CH₂COO⁻ B⁺ (at pH=12) B⁺=arbitrary cation, for example Na⁺    -   esterquats

Quaternary surfactants contain at least one N atom that is covalentlybonded to 4 alkyl or aryl groups. This leads to a positive charge,irrespective of the pH value. Alkylbetaine, alkylamidopropylbetaine andalkylamidopropylhydroxysulfaine are advantageous. The cationicsurfactants used can furthermore preferably be chosen from the groupcomprising the quaternary ammonium compounds, in particularbenzyltrialkyl-ammonium chloride or bromide, such as, for example,benzyldimethylstearyl-ammonium chloride, and also alkyltrialkyl-ammoniumsalts, for example cetyltrimethylammonium chloride or bromide,alkyldimethylhydroxyethylammonium chlorides or bromides,dialkyldimethylammonium chlorides or bromides,alkylamidoethyl-trimethyl-ammonium ether sulphates, alkylpyridiniumsalts, for example lauryl- or cetylpyrimidinium chloride, imidazolinederivatives and compounds of a cationic nature, such as amine oxides,for example alkyldimethylamine oxides or alkylaminoethyldimethylamineoxides. Cetyltrimethylammonium salts can be used particularlyadvantageously.

C. Amphoteric Surfactants

Amphoteric surfactants that can advantageously be used are

-   -   acyl-/dialkylethylenediamine, for example sodium        acylampho-acetate, disodium acylamphodipropionate, disodium        alkylampho-diacetate, sodium acylamphohydroxypropylsulphonate,        disodium acylamphodiacetate and sodium acylamphopropionate,    -   N-alkylamino acids, for example aminopropylalkylglutamide,        alkyl-aminopropionic acid, sodium alkylimidodipropionate and        lauro-amphocarboxyglycinate.        D. Non-Ionic Surfactants

Non-ionic surfactants that can advantageously be used are

-   -   alcohols,    -   alkanolamides, such as cocamides MEA/DEA/MIPA,    -   amine oxides, such as cocoamidopropylamine oxide,    -   esters, that are formed by esterification of carboxylic acids        with ethylene oxide, glycerol, sorbitan or other alcohols,    -   ethers, for example ethoxylated/propoxylated alcohols,        ethoxylated/propoxylated esters, ethoxylated/propoxylated        glycerol esters, ethoxylated/propoxylated cholesterols,        ethoxylated/propoxylated triglyceride esters,        ethoxylated/propoxylated lanolin, ethoxylated/propoxylated        polysiloxanes, propoxylated POE ethers and alkylpolyglycosides,        such as lauryl glucoside, decyl glycoside and coco glycoside.    -   sucrose esters and ethers    -   polyglycerol esters, diglycerol esters, monoglycerol esters    -   methylglucose esters, ester of hydroxy acids

The use of a combination of anionic and/or amphoteric surfactants withone or more non-ionic surfactants is also advantageous. Thesurface-active substance can be present in a concentration of between 1and 98% (m/m) in the formulations containing histamine releaseinhibitors according to the invention, based on the total weight of theformulations.

Cosmetic or dermatological formulations that contain histamine releaseinhibitors according to the invention can also be in the form ofemulsions.

The oil phase can advantageously be chosen from the following group ofsubstances:

-   -   mineral oils, mineral waxes    -   fatty oils, fats, waxes and other natural and synthetic fatty        bodies, preferably esters of fatty acids with alcohols having a        low C number, for example with isopropanol, propylene glycol or        glycerol, or esters of fatty alcohols with alkanoic acids having        a low C number or with fatty acids;    -   alkyl benzoates;    -   silicone oils, such as dimethylpolysiloxanes,        diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms        therefrom.

Advantageously, esters of saturated and/or unsaturated, branched and/orstraight-chain alkanecarboxylic acids having a chain length of 3 to 30 Catoms and saturated and/or unsaturated, branched and/or straight-chainalcohols having a chain length of 3 to 30 C atoms, from the group ofesters of aromatic carboxylic acids and saturated and/or unsaturated,branched and/or straight-chain alcohols having a chain length of 3 to 30C atoms can be used. Preferred ester oils are isopropyl myristate,isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butylstearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononylstearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyllaurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate,oleyl erucate, erucyl oleate, erucyl erucate and synthetic,semi-synthetic and natural mixtures of such esters, for example, jojobaoil.

Furthermore, the oil phase can advantageously be chosen from the groupcomprising the branched and straight-chain hydrocarbons and waxes, thesilicone oils, the dialkyl ethers, the group comprising the saturated orunsaturated, branched or straight-chain alcohols, and also the fattyacid triglycerides, specifically, the triglycerol esters of saturatedand/or unsaturated, branched and/or straight-chain alkanecarboxylicacids having a chain length of 8 to 24, in particular 12 to 18 C atoms.The fatty acid triglycerides can, for example, advantageously be chosenfrom the group comprising the synthetic, semi-synthetic and naturaloils, for example, olive oil, sunflower oil, soya oil, peanut oil,rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil andmore of the like. Arbitrary admixtures of such oil and wax componentscan also advantageously be used. In some cases it is also advantageousto use waxes, for example cetyl palmitate, as the sole lipid componentof the oil phase; advantageously, the oil phase is chosen from the groupthat consists of 2-ethylhexyl isostearate, octyldodecanol, isotridecylisononanoate, isoeicosane, 2-ethylhexyl cocoate, C₁₂₋₁₅-alkyl benzoate,capryl-capric acid triglyceride and dicaprylyl ether. Mixtures ofC₁₂₋₁₅-alkyl benzoate and 2-ethylhexyl isostearate, mixtures ofC₁₂₋₁₅-alkyl benzoate and isotridecyl isononanoate and mixtures ofC₁₂₋₁₅-alkyl benzoate, 2-ethylhexyl isostearate and isotridecylisononanoate are particularly advantageous. The hydrocarbons paraffinoil, squalane and squalene can oh (sic) advantageously be used.Advantageously, the oil phase can furthermore contain cyclic or linearsilicone oils or consist entirely of such oils, it being, however,preferred to use an additional content of other oil phase components inaddition to the silicone oil or the silicone oils. Cyclomethicone (forexample, decamethylcyclopentasiloxane) can advantageously be used assilicone oil. However, other silicone oils can also advantageously beused, for example undecamethylcyclotrisiloxane, polydimethylsiloxane andpoly(methyl-phenylsiloxane). Furthermore, mixtures of cyclomethicone andisotridecyl isononanoate and of cyclomethicone and 2-ethylhexylisostearate are particularly advantageous.

The aqueous phase of formulations that contain histamine releaseinhibitors according to the invention and are in the form of an emulsioncan comprise: alcohols, diols or polyols having a low C number and alsothe ethers thereof, preferably ethanol, isopropanol, propylene glycol,glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether,propylene glycol monomethyl, monoethyl or monobutyl ether, diethyleneglycol monomethyl or monoethyl ether and analogous products, and alsoalcohols having a low C number, for example, ethanol, isopropanol,1,2-propanediol, glycerol and also, in particular, one or morethickeners, which thickener or thickeners can advantageously be chosenfrom the group comprising silicon dioxide, aluminium silicates,polysaccharides and the derivatives thereof, for example hyaluronicacid, xanthan gum, hydroxypropyl-methylcellulose, and particularlyadvantageously from the group comprising the polyacrylates, preferably apolyacrylate from the group comprising the so-called carbopols, forexample carbopols of types 980, 981, 1382, 2984, 5984, in each case ontheir own or in combination.

Formulations that contain histamine release inhibitors according to theinvention and are in the form of an emulsion advantageously contain oneor more emulsifiers. O/W emulsifiers can, for example, advantageously bechosen from the group comprising the polyethoxylated or polypropoxylatedor polyethoxylated and polypropoxylated products, for example:

-   -   the fatty alcohol ethoxylates    -   the ethoxylated wool wax alcohols,    -   the polyethylene glycol ethers of the general formula        R—O—(—CH₂—CH₂—O—)_(n)—R′,    -   the fatty acid ethoxylates of the general formula        R—COO—(—CH₂—CH₂—O—)_(n)—H,    -   the etherified fatty acid ethoxylates of the general formula        R—COO—(—CH₂—CH₂—O—)_(n)—R′,    -   the esterified fatty acid ethoxylates of the general formula        R—COO—(—CH₂—CH₂—O—)_(n)—C(O)—R′,    -   the polyethylene glycol glycerol fatty acid esters    -   the ethoxylated sorbitan esters    -   the cholesterol ethoxylates    -   the ethoxylated triglycerides    -   the alkyl ether carboxylic acids of the general formula        R—COO—(—CH₂—CH₂—O—)_(n)—OOH, and n represent (sic) a number from        5 to 30,    -   the polyoxyethylene sorbitol fatty acid esters,    -   the alkyl ether sulphates of the general formula        R—O—(—CH₂—CH₂—O—)_(n)—SO₃—H    -   the fatty alcohol propoxylates of the general formula        R—O—(—CH₂—CH(CH₃)—O—)_(n)—H    -   the polypropylene glycol ethers of the general formula        R—O—(—CH₂—CH(CH₃)—O—)_(n)—R′    -   the propoxylated wool wax alcohols,    -   the esterified fatty acid propoxylates        R—COO—(—CH₂—CH(CH₃)—O—)_(n—R′)    -   the esterified fatty acid propoxylates of the general formula        R—COO—(—CH₂—CH(CH₃)—O—)_(n)—C(O)—R′    -   the fatty acid propoxylates of the general formula        R—COO—(—CH₂—CH(CH₃)—O—)_(n)—H,    -   the polypropylene glycol glycerol fatty acid esters    -   the propoxylated sorbitan esters    -   the cholesterol propoxylates    -   the propoxylated triglycerides    -   the alkyl ether carboxylic acids of the general formula        R—O—(—CH₂—CH(CH₃)—O—)_(n)—CH₂—COOH,    -   the alkyl ether sulphates and the acids on which these sulphates        are based of the general formula        R—O—(—CH₂—CH(CH₃)—O—)_(n)—SO₃—H,    -   the fatty alcohol ethoxylates/propoxylates of the general        formula R—O—X_(n)—Y_(m)—H    -   the polypropylene glycol ethers of the general formula        R—O—X_(n)—Y_(m)—R′    -   the esterified fatty acid propoxylates of the general formula        R—COO—X_(n)—Y_(m)—R′    -   the fatty acid ethoxylates/propoxylates of the general formula        R—COO—X_(n)—Y_(m)—H.

According to the invention, the polyethoxylated or polypropoxylated orpolyethoxylated and polypropoxylated O/W emulsifiers used areparticularly advantageously chosen from the group comprising substanceshaving HLB values of 11-18, very particularly advantageously having HLBvalues of 14.5-15.5, insofar as the O/W emulsifiers contain saturatedradicals R and R′. If the O/W emulsifiers contain unsaturated radicals Rand/or R′, or if there are isoalkyl derivatives, the preferred HLB valueof such emulsifiers can also be lower or higher.

It is advantageous to choose the fatty alcohol ethoxylates from thegroup comprising the ethoxylated stearyl alcohols, cetyl alcohols,cetylstearyl alcohols (cetearyl alcohols). The following areparticularly preferred:

-   polyethylene glycol(13) stearyl ether (Steareth-13),-   polyethylene glycol(14) stearyl ether (Steareth-14),-   tpolyethylene glycol(15) stearyl ether (Steareth-15),-   polyethylene glycol(16) stearyl ether (Steareth-16),-   polyethylene glycol(17) stearyl ether (Steareth-17),-   polyethylene glycol(18) stearyl ether (Steareth-18),-   polyethylene glycol(19) stearyl ether (Steareth-19),-   polyethylene glycol(20) stearyl ether (Steareth-20),-   polyethylene glycol(12) isostearyl ether (Isosteareth-12),-   polyethylene glycol(13) isostearyl ether (Isosteareth-13),-   polyethylene glycol(14) isostearyl ether (Isosteareth-14),-   polyethylene glycol(15) isostearyl ether (Isosteareth-15),-   polyethylene glycol(16) isostearyl ether (Isosteareth-16),-   polyethylene glycol(17) isostearyl ether (Isosteareth-17),-   polyethylene glycol(18) isostearyl ether (Isosteareth-18),-   polyethylene glycol(19) isostearyl ether (Isosteareth-19),-   polyethylene glycol(20) isostearyl ether (Isosteareth-20),-   polyethylene glycol(13) cetyl ether (Ceteth-13),-   polyethylene glycol(14) cetyl ether (Ceteth-14),-   polyethylene glycol(15) cetyl ether (Ceteth-15),-   polyethylene glycol(16) cetyl ether (Ceteth-16),-   polyethylene glycol(17) cetyl ether (Ceteth-17),-   polyethylene glycol(18) cetyl ether (Ceteth-18),-   polyethylene glycol(19) cetyl ether (Ceteth-19),-   polyethylene glycol(20) cetyl ether (Ceteth-20),-   polyethylene glycol(13) isocetyl ether (Isoceteth-13),-   polyethylene glycol(14) isocetyl ether (Isoceteth-14),-   polyethylene glycol(l15) isocetyl ether (Isoceteth-15),-   polyethylene glycol(16) isocetyl ether (Isoceteth-16),-   polyethylene glycol(17) isocetyl ether (Isoceteth-17),-   polyethylene glycol(18) isocetyl ether (Isoceteth-18),-   polyethylene glycol(19) isocetyl ether (Isoceteth-19),-   polyethylene glycol(20) isocetyl ether (Isoceteth-20),-   polyethylene glycol(12) oleyl ether (Oleth-12),-   polyethylene glycol(13) oleyl ether (Oleth-13),-   polyethylene glycol(14)oleyl ether (Oleth-14),-   polyethylene glycol(15)oleyl ether (Oleth-15),-   polyethylene glycol(12) lauryl ether (Laureth-12),-   polyethylene glycol(12) isolauryl ether (Isolaureth12),-   polyethylene glycol(13) cetyl stearyl ether (Ceteareth-13),-   polyethylene glycol(14) cetyl stearyl ether (Ceteareth-14),-   polyethylene glycol(15) cetyl stearyl ether (Ceteareth-15),-   polyethylene glycol(16) cetyl stearyl ether (Ceteareth-16),-   polyethylene glycol(17) cetyl stearyl ether (Ceteareth-17),-   polyethylene glycol(18) cetyl stearyl ether (Ceteareth-18),-   polyethylene glycol(19) cetyl stearyl ether (Ceteareth-19),-   polyethylene glycol(20) cetyl stearyl ether (Ceteareth-20).

It is furthermore advantageous to choose the fatty acid ethoxylates fromthe following group:

-   polyethylene glycol(20) stearate,-   polyethylene glycol(21) stearate,-   polyethylene glycol(22) stearate,-   polyethylene glycol(23) stearate,-   polyethylene glycol(24) stearate,-   polyethylene glycol(25) stearate,-   polyethylene glycol(12) isostearate,-   polyethylene glycol(13) isostearate,-   polyethylene glycol(14) isostearate,-   polyethylene glycol(15) isostearate,-   polyethylene glycol(16) isostearate,-   polyethylene glycol(17) isostearate,-   polyethylene glycol(18) isostearate,-   polyethylene glycol(19) isostearate,-   polyethylene glycol(20) isostearate,-   polyethylene glycol(21) isostearate,-   polyethylene glycol(22) isostearate,-   polyethylene glycol(23) isostearate,-   polyethylene glycol(24) isostearate,-   polyethylene glycol(25) isostearate,-   polyethylene glycol(12) oleate,-   polyethylene glycol(13) oleate,-   polyethylene glycol(14) oleate,-   polyethylene glycol(15) oleate,-   polyethylene glycol(16) oleate,-   polyethylene glycol(17) oleate,-   polyethylene glycol(18) oleate,-   polyethylene glycol(19) oleate,-   polyethylene glycol(20) oleate.

Advantageously, sodium laureth-11-carboxylate can be used as ethoxylatedalkyl ether carboxylic acid or the salt thereof. Sodium laureth 1-4sulphate can advantageously be used as alkyl ether sulphate.Polyethylene glycol(30) cholesteryl ether can advantageously be used asethoxylated cholesterol derivative. Polyethylene glycol(25) soyasterolhas also proved useful.

The polyethylene glycol(60) evening primrose glycerides canadvantageously be used as ethoxylated triglycerides.

It is furthermore advantageous to choose the polyethylene glycolglycerol fatty acid esters from the group comprising polyethyleneglycol(20) glyceryl laurate,

-   polyethylene glycol(21) glyceryl laurate,-   polyethylene glycol(22) glyceryl laurate,-   polyethylene glycol(23) glyceryl laurate,-   polyethylene glycol(6) glyceryl caprate/caprinate,-   polyethylene glycol(20) glyceryl oleate,-   polyethylene glycol(20) glyceryl isostearate,-   polyethylene glycol(18) glyceryl oleate/cocoate.

It is also advantageous to choose the sorbitan esters from the groupcomprising

-   polyethylene glycol(20) sorbitan monolaurate,-   polyethylene glycol(20) sorbitan monostearate,-   polyethylene glycol(20) sorbitan monoisostearate,-   polyethylene glycol(20) sorbitan monopalmitate,-   polyethylene glycol(20) sorbitan monooleate.

The following can be used as advantageous W/O emulsifiers: fattyalcohols having 8 to 30 carbon atoms, monoglycerol esters of saturatedand/or unsaturated, branched and/or straight-chain alkanecarboxylicacids having a chain length of 8 to 24, in particular 12 to 18 C atoms,diglycerol esters of saturated and/or unsaturated, branched and/orstraight-chain alkanecarboxylic acids having a chain length of 8 to 24,in particular 12 to 18 C atoms, monoglycerol ethers of saturated and/orunsaturated, branched and/or straight-chain alcohols having a chainlength of 8 to 24, in particular 12 to 18 C atoms, diglycerol ethers ofsaturated and/or unsaturated, branched and/or straight-chain alcoholshaving a chain length of 8 to 24, in particular 12 to 18 C atoms,propylene glycol esters of saturated and/or unsaturated, branched and/orstraight-chain alkanecarboxylic acids having a chain length of 8 to 24,in particular 12 to 18 C atoms and sorbitan esters of saturated and/orunsaturated, branched and/or straight-chain alkanecarboxylic acidshaving a chain length of 8 to 24, in particular 12 to 18 C atoms.

Particularly advantageous W/O emulsifiers are glyceryl monostearate,glyceryl monoisostearate, glyceryl monomyristate, glyceryl monooleate,diglyceryl monostearate, diglyceryl monoisostearate, propylene glycolmonostearate, propylene glycol monoisostearate, propylene glycolmonocaprylate, propylene glycol monolaurate, sorbitan mono-isostearate,sorbitan monolaurate, sorbitan monocaprylate, sorbitan monoisooleate,sucrose distearate, cetyl alcohol, stearyl alcohol, arachidyl alcohol,behenyl alcohol, isobehenyl alcohol, selachyl alcohol, chimyl alcohol,polyethylene glycol(2) stearyl ether (Steareth-2), glyceryl monolaurate,glyceryl monocaprinate, glyceryl monocaprylate.

The substance of the Formula 1 according to the invention can also beused as a constituent of perfume compositions (fragrance compositions)and, because of its specific activity, as an inhibitor of substanceP-induced release of histamine from mast cells can, for example, impartan anti-allergic or itch-alleviating action to a perfumed finishedproduct. A particularly preferred fragrance composition comprises (a) afragrance in an amount that has a sensory action, (b) an amount of oneor more compounds of the Formula 1 that has, for example ananti-allergic or itch-alleviating action and (c) optionally one or moreexcipients and/or additives. Since the proportion of perfume in acosmetic finished product is frequently in the region of approximately1% (m/m), a perfume which contains a compound of the Formula 1 accordingto the invention will preferably consist of approximately 0.1-10% (m/m)of one or more compounds of the Formula 1. It has proved particularlyadvantageous that the substances of the Formula 1 have only a weakinherent odour or are even completely odourless; since thischaracteristic predestines them in particular for use as inhibitors ofthe substance P-induced release of histamine from mast cells in afragrance composition.

Preferred embodiments and further aspects of the present invention canbe seen from the appended patent claims. TABLE 1a % inhibition No.Structural formula 0.5 ppm 5 ppm 50 ppm 2

7 80 108 3

11 62 106 4

3 49 59 5

7 17 47 6

−9 1 41 7

27 26 40 8

13 26 40 9

11 19 39 10

−10 8 37 11

−6 11 36 12

−5 0 34 13

17 2 30 14

21 30 24 15

23 22 21 16

26 25 7 17

4 7 6 18

5 −3 6 19

−15 −22 −4

TABLE 1b % inhibition No. Structural formula 0.5 ppm 5 ppm 50 ppm 20

14 76 110 21

−15 48 76 22

39 72 71 23

9 29 69 24

7 19 55 25

8 42 51 26

−13 22 48 27

27 28 39 28

12 25 35 29

−1 15 23

TABLE 2 GS101100-A: Anthranilic acid amide fraction from cultivated oatsextract Anthranilic acid amide content (sum of avenanthramides 3, 4 and5) = 500 ppm in glycerol GS101100-B: Rconstituted product consisting ofsynthetic avenathramides 3, 4 and 5 Anthranilic acid amide content (sumof synthetic avenanthramides 3, 4 and 5) = 500 ppm in glycerol %inhibition No. Structural formula 0.5 ppm 5 ppm 50 ppm GS101100-ACultivated oats extract fraction 57.80 30.00 111.30 GS101100-B

1.20 30.50 116.50

TABLE 3 No. Structural formula Chemical name 5

5-hydroxy-2-{[3-(4- hydroxyphenyl)propano- yl]amino)benzoic acid 8

2-{[3-(4- hydroxyphenyl)propano- yl]amino}benzoic acid 11

5-hydroxy-2-{[3-(3,4- dimethoxyphenyl)propa- noyl]amino}benzoic acid 20

2-[(3,4-dihydroxy benzoyl)amino]benzoic acid 22

2-[(3,4,5-trihydroxy- benzoyl)amino]benzoic acid 23

2-[(3-hydroxy-4- methoxybenzoyl)amino]- benzoic acid 24

2-[(4-hydroxy- benzoyl)amino]benzoic acid 25

2-[(4-hydroxy-3- methoxybenzoyl)amino]- benzoic acid 28

2-[(3-hydroxy- benzoyl)amino]benzoic acid 36

2-{[3-(3,4-dihydroxy- phenyl)propano- yl]amino}benzoic acid 37

5-hydroxy-2-{[3-(3,4- dihydroxyphenyl)propa- noyl]amino}benzoic acid 38

4-hydroxy-2-{[3-(3,4- dihydroxyphenyl)propa- noyl]amino}benzoic acid 39

2-{[3-(4-hydroxy-3- methoxyphenyl)propa- noyl]amino}benzoic acid 40

5-hydroxy-2-{(3-(4- hydroxy-3-methoxy- phenyl)propano- yl]amino}benzoicacid 41

4-hydroxy-2-{[3-(4- hydroxy-3-methoxy- phenyl)propano- yl]amino}benzoicacid 42

4-hydroxy-2-{[3-(4- hydroxyphenyl)propano- yl]amino}benzoic acid 43

5-hydroxy-2-{[3-(3- hydroxy-4-methoxy- phenyl)allano- yl]amino}benzoicacid 44

4-hydroxy-2-{[3-(3- hydroxy-4-methoxy- phenyl)allano- yl]amino}benzoicacid 45

2-{[3-(3-hydroxy-4- methoxyphenyl)propano- yl]amino}benzoic acid 46

5-hydroxy-2-{[3-(3- hydroxy-4-methoxy- phenyl)propano- yl]amino}benzoicacid 47

4-hydroxy-2-{[3-(3- hydroxy-4-methoxy- phenyl)propano- yl]amino}benzoicacid 48

2-{[3-(2,4-dihydroxy- phenyl)allano- yl]amino}benzoic acid 49

2-{[3-(2,4-dihydroxy- phenyl)propano- yl]amino}benzoic acid 50

5-hydroxy-2-{[3-(2,4- dihydroxyphenyl)allano- yl]amino}benzoic acid 51

5-hydroxy-2-{[3-(2,4- dihydroxyphenyl)propa- noyl]amino}benzoic acid 52

4-hydroxy-2-{[3-(2,4- dihydroxyphenyl)allano- yl]amino}benzoic acid 53

4-hydroxy-2-{[3-(2,4- dihydroxyphenyl)propa- noyl]amino}benzoic acid 54

2-{[3-(3- hydroxyphenyl)allano- yl]amino}benzoic acid 55

2-{[3-(3- hydroxyphenyl)propano- yl]amino}benzoic acid 56

5-hydroxy-2-{[3-(3- hydroxyphenyl)allano- yl]amino}benzoic acid 57

5-hydroxy-2-{[3-(2,4- dihydroxyphenyl)propa- noyl]amino benzoic acid 58

4-hydroxy-2-{[3-(3- hydroxyphenyl)allano- yl]amino}benzoic acid 59

4-hydroxy-2-{[3-(2,4- dihydroxyphenyl)propa- noyl]amino}benzoic acid 60

2-{[3-(2- hydroxyphenyl)allano- yl]amino}benzoic acid 61

2-{[3-(2- hydroxyphenyl)propano- yl]amino}benzoic acid 62

5-hydroxy-2-{[3-(2- hydroxyphenyl)allano- yl]amino}benzoic acid 63

5-hydroxy-2-{[3-(2- hydroxyphenyl)propano- yl]amino}benzoic acid 64

4-hydroxy-2-{[3-(2- hydroxyphenyl)allano- yl]amino}benzoic acid 65

4-hydroxy-2-{[3-(2- hydroxyphenyl)propano- yl]amino}benzoic acid 66

5-hydroxy-2-[(3,4,5- trihydroxybenzo- yl)amino]benzoic acid 67

4-hydroxy-2-[(3,4,5- trihydroxybenzo- yl)amino]benzoic acid 68

5-hydroxy-2-[(3,4- dihydroxybenzo- yl)amino]benzoic acid 69

4-hydroxy-2-[(3,4- dihydroxybenzo- yl)amino]benzoic acid 70

5-hydroxy-2-[(2,4- dihydroxybenzo- yl)amino]benzoic acid 71

5-hydroxy-2-[(3-hydroxy- 4-methoxy- benzoyl)amino]benzoic acid 72

4-hydroxy-2-[(3-hydroxy- 4-methoxy- benzoyl)amino]benzoic acid 73

5-hydroxy-2-[(4-hydroxy- 3-methoxy- benzoyl)amino]benzoic acid 74

4-hydroxy-2-[(4-hydroxy- 3-methoxy- benzoyl)amino]benzoic acid 75

4-hydroxy-2-[(4- hydroxybenzoyl)amino]- benzoic acid 76

5-hydroxy-2-[(3- hydroxybenzoyl)amino]- benzoic acid 77

4-hydroxy-2-[(3- hydroxybenzoyl)amino]- benzoic acid 78

5-hydroxy-2-[(2- hydroxybenzoyl)amino]- benzoic acid 79

5-hydroxy-2- [(benzoyl)amino]benzoic acid 80

4-hydroxy-2- [(benzoyl)amino]benzoic acid

TABLE 4 No. Structural formula CAS no. 2

116764-16-0 3

116764-15-9 4

108605-69-2 6

116764-17-1 7

108605-70-5 9

93755-77-2 10

115610-36-1 12

207742-91-4 13

188545-62-2 21

110846-17-8 26

115610-37-2 27

579-93-1 29

13316-98-8 30

448029-17-0 31

116764-18-2 32

116764-19-3 33

80530-43-4 34

115610-38-3 35

115610-40-7

1. A process for inhibiting substance P-induced release of histaminefrom mast cells by treating said mast cells with a compound of theFormula 1 or of a mixture of two or more different compounds of theFormula 1,

where for the compound or each compound of the mixture: m=0, 1, 2or 3,p=0, 1 or 2, n=0, 1 or 2, with the proviso that, when n=1 or 2, the sumof p+m>0, where, when n=1 or 2, R¹ and R², in each case in pairs, ineach case denote H or together denote a further chemical bond; where,when m=1, 2 or 3, each X, independently of the others, denotes OH,Oalkyl or Oacyl, where, when p=1 or 2, each Y, independently of theothers, denotes OH, Oalkyl or Oacyl, with the proviso that, when p+m>0,X or Y has been selected at least once from the group that consists ofOH and Oacyl; R³═H or alkyl.
 2. A process according to claim 1, where:n=1 and m=1, 2 or 3, with the proviso that X has been selected at leastonce from the group that consists of OH or Oacyl, and/or p=1 or 2, withthe proviso that Y has been selected at least once from the group thatconsists of OH and Oacyl.
 3. A process according to claim 1, where: n=1and R¹ and R² each denote H.
 4. A process according to claim 2, whereinthe compound of the Formula 1 has been selected from the group thatconsists of:


5. A process according to claim 1, where: n=0.
 6. A process according toclaim 5, wherein the compound of the Formula 1 has been selected fromthe group that consists of:


7. A process for treating or preventing pruritus, skin reddening, wealdevelopment or allergic skin reactions by treating skin containing mastcells with a compound of the Formula 1 or of a mixture of two or moredifferent compounds of the Formula 1,

where for the compound or each compound in the mixture: m=0, 1, 2 or 3,p=0, 1 or 2, n=0, 1 or 2, with the proviso that, when n=1 or 2, the sumof p+m>0, where, when n=1 or 2, R¹ and R², in each case in pairs, ineach case denote H or together denote a further chemical bond; where,when m=1, 2 or 3, each X, independently of the others, denotes an OH,Oalkyl or Oacyl, where, when p=1 or 2, each Y, independently of theothers, denotes OH, Oalkyl or Oacyl, with the proviso that, when p+m>0,X or Y has been selected at least once from the group that consists ofOH and Oacyl; R³═H or alkyl.
 8. A process according to claim 7, where:n=1, m+p>2 with the proviso that X and Y together have been selected atleast twice from the group that consists of OH and Oacyl.
 9. A processaccording to claim 8, wherein the compound of the Formula 1 has beenselected from the group that consists of:


10. A process according to claim 7, where: n=1 and R¹ and R² each denoteH.
 11. A process according to claim 7, where: n=0.
 12. A processaccording to claim 11, where: m+p>2, with the proviso that at least twoof the substituents X and Y have been selected from the group thatconsists of OH and Oacyl.
 13. A process according to claim 1, whereinthe compound of the Formula 1 is in the form of a constituent of a plantextract.
 14. A process according to claim 13, wherein the plant extractis an extract from plants of the genus Avena, Dianthus, Silene orMelandrium.
 15. A process according to claim 13, wherein the plantextract has been concentrated in such a way that the proportion of atleast one compound of the Formula 1 relative to the proportion of otherextracted compounds is increased compared with the extract that has notbeen concentrated.
 16. A process according to claim 1, comprising anisolated and purified compound of the Formula
 1. 17. Compound of theFormula 1,

where: m=0, 1, 2 or 3, p=0, 1 or 2, n=1, with the proviso that the sumof p+m>0, where R¹ and R², in each case in pairs, in each case denote Hor together denote a further chemical bond; where, when m=1, 2 or 3,each X, independently of the others, denotes OH, Oalkyl or Oacyl, where,when p=1 or 2, each Y, independently of the others, denotes OH, Oalkylor Oacyl, with the proviso that X or Y has been selected at least oncefrom the group that consists of OH and Oacyl; R³═H or alkyl. 18.Compound of the Formula 1,

where: m=0, 1, 2 or 3, p=0, 1 or 2, n=0, where R¹ and R², in each casein pairs, in each case denote H or together denote a further chemicalbond: where, when m=1, 2 or 3, each X, independently of the others,denotes OH, Oalkyl or Oacyl, where, when p=1 or 2, each Y, independentlyof the others, denotes OH, Oalkyl or Oacyl, with the proviso that, whenp+m>0, X or Y has been selected at least once from the group thatconsists of OH and Oacyl; R³═H or alkyl.
 19. A compound according toclaim 17 selected from the group consisting of:


20. A compound according to claim 18 selected from the group consistingof:


21. A process according to claim 1 wherein said mast cells are treatedwith a mixture of two or more different compounds having a structureaccording to Formula 1.